WO2010014651A1 - Marqueurs pharmacogénétiques de la prédisposition à la toxicité médicamenteuse pancréatique - Google Patents

Marqueurs pharmacogénétiques de la prédisposition à la toxicité médicamenteuse pancréatique Download PDF

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Publication number
WO2010014651A1
WO2010014651A1 PCT/US2009/052019 US2009052019W WO2010014651A1 WO 2010014651 A1 WO2010014651 A1 WO 2010014651A1 US 2009052019 W US2009052019 W US 2009052019W WO 2010014651 A1 WO2010014651 A1 WO 2010014651A1
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WO
WIPO (PCT)
Prior art keywords
patient
polymorphic site
drug
seq
snp
Prior art date
Application number
PCT/US2009/052019
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English (en)
Inventor
Jeffery Kutok
Carol Waghorne
Lewis Silverman
Original Assignee
The Brigham And Women's Hospital, Inc.
Dana-Farber Cancer Institute, Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Brigham And Women's Hospital, Inc., Dana-Farber Cancer Institute, Inc filed Critical The Brigham And Women's Hospital, Inc.
Publication of WO2010014651A1 publication Critical patent/WO2010014651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/142—Toxicological screening, e.g. expression profiles which identify toxicity

Definitions

  • the present invention is directed to genetic assays that can be used to predict the susceptibility of a patient for the development of drug-induced pancreatic toxicity.
  • the assays are based primarily on specific single nucleotide polymorphisms in the noncoding region of the calcium sensing receptor gene.
  • the present invention is based upon the discovery that analysis of single nucleotide polymorphisms (SNPs) in the human calcium sensing receptor gene can be used to identify patients that are at increased risk of developing pancreatitis or other pancreatic conditions in response to drug administration. Patients with certain allelic profiles at these SNPs are more susceptible to pancreatic complications in response to drug administration and should, preferably, be treated with drugs that are relatively nontoxic to the pancreas.
  • SNPs single nucleotide polymorphisms
  • SNP sequences as well as the sequence for the human calcium sensing receptor gene are known in the art and may be found by reference to National Center for Biotechnology
  • rs2134221 AATAACCAGAATATTACAAGCTCTAACAGCTCTATAGGAAAAACATCTAATAAT CCGATTTAAAATGGGTAAAAGATCTGAATAGACCTTTCTCAAAAGAAGACATAT GA[AZG]TATGAAACAGGAATATGAAAAGGTGCTCAACATCACTGATCATCAAAG TAATGCAAATCAAAACTACAGTGAGATATCATCTCACCCCAGTTAAAATGGCTT TTATCCAA (SEQ ID NO: 1);
  • the nucleotide change characteristic of the polymorphism is at a site
  • allelic profile of a patient refers to the sequences that a patient has at each allele for a particular SNP.
  • a patient may have an A:A, A:G, or G:G allelic profile.
  • the invention is directed to a method for identifying a patient at increased risk for developing pancreatic toxicity in response to the administration of a drug.
  • the method involves performing an assay to determine whether the patient has an SNP profile that is associated with reduced calcium sensing receptor activity (e.g., by reducing gene expression). If such a profile is detected, it may be concluded that the patient is at increased risk.
  • the term "increased risk” means that, relative to either the population in general or, more specifically, to people without the SNP profile, patients have a higher incidence of pancreatic toxicity. Toxicity may be determined by running well recognized tests for pancreatic enzymes and will manifest itself as increases in pancreatic conditions such as pancreatitis.
  • Specific SNP sequences that may be evaluated as predictors of increased risk are rs2134221; rs4678188; and rs6802834.
  • Specific allelic combinations that are associated with increased risk are: for rs2134221, A:G (i.e., patients having one allele with A at the polymorphic site and one allele with G at the polymorphic site are at increased risk); for rs4678188, C:T; and for rs6802834, A:G. Relevant results in this regard may be found in Table 2.
  • Patients that may receive drugs leading to pancreatitis include cancer patients receiving chemotherapy, especially patients with acute lymphoblastic leukemia.
  • specific drugs that may be administered to patients and lead to pancreatic toxicity include: acetaminophen; azathioprinc; carbamazcpine; cisplatin: cytarabinc; didanosinc; enafapril; erythromycin; estrogens; furosemide; hydrochloro-thiazide; interferon-alpha; lamivudinc; mesaiamine; 6-mcrcaptopurine; octreotide; opioids; oral contraceptives; pentamidine; rifampin; steroids; sulfamethoxazole with trimethoprim; sulindac; sulfasalazine: tetracycline; valproic acid and, especially asparaginase.
  • any method of determining the SNP sequences present in a patient's genome may be used in connection with the present invention.
  • assays performed by amplifying genomic DNA by the polymerase chain reaction (PCR) using primers that flank the genomic site where the SNP occurs, followed by sequencing are generally preferred.
  • kits that can be used to evaluate the SNPs noted above and that include oligonucleotides that can serve as primers for the PCR amplification of rs2134221, rs4678188 and/or rs6802834.
  • Kits should have at least one oligonucleotide with a sequence 15-100 nucleotides long lying 5' to the polymorphic site shown in SEQ ID NO:1; and/or at least one oligonucleotide with a sequence 15-100 nucleotides long lying 5' to the polymorphic site shown in SEQ ID NO:2; and/or at least one oligonucleotide with a sequence 15-100 nucleotides long lying 5' to the polymorphic site shown in SEQ ID NO:3.
  • the sequences of the oligonucleotides should be identical to a sequence shown in SEQ ID NO:1, 2 or 3.
  • the oligonucleotides are 15-50 nucleotides in length. Kits may also include oligonucleotides 15-50 nucleotides long that lie 3' to the polymorphic site of the rs2134221, rs4678188 and rs6802834 SNPs.
  • the present invention is based upon an association between sequence variations occurring in the human calcium sensing receptor (CASR) gene and the likelihood that a patient will develop conditions such as pancreatitis as a drug side effect.
  • CCR human calcium sensing receptor
  • Methods for genotyping individuals to determine specific polymorphic sequences are well established in the art. Typically, these methods involve a step in which relevant sequences are amplified by PCR. Primers for amplification can be chosen using methods known in the art, with specific sequences being based on the genomic sequences that have been established for the CASR gene and that are available in reference databases such as those maintained by NCBI.
  • Microarrays may also be used in assays for the presence of SNPs. For example, sequences that match the known sequences for rs2134221, rs4678188 and rs6802834 may be immobilized on plates. Hybridizations carried out under conditions of high stringency (low salt, e.g., 0.1-0.5x SSC, and high temperature , e.g., 5O 0 C - 68 0 C) may then be used to determine whether a corresponding sequence exists in a sample.
  • high stringency low salt, e.g., 0.1-0.5x SSC
  • high temperature e.g., 5O 0 C - 68 0 C
  • a case-control study was performed to examine the association between genetic polymorphisms in candidate genes in Acute Lymphoblastic Leukemia patients with drug- induced pancreatitis.
  • DNA from 49 cases of patients with ASP-induced pancreatitis and 87 matched controls were used for this study.
  • candidate genes identified from the literature as being strongly associated with susceptibility to pancreatitis were genotyped for 1-12 common haplotyped-tagged single nucleotide polymorphisms (SNP) (see Table 1). The data obtained from this analysis showed that only three SNPs showed highly statistically significant differences in allelic frequency between the case and control groups.
  • SNP single nucleotide polymorphisms
  • SNPs are present within the non-coding regions of the Calcium Sensing Receptor (CASR) and included rs2134221 (p ⁇ 0.0008), rs4678188 (p ⁇ 0.001), and rs6802834 (p ⁇ 0.002) (Table 2).
  • CASR functions in "sensing" minute alterations in Ca 2+ through the actions of PTH on the effector elements of calcium homeostasis (i.e., kidney, bone, and intestine). Inactivating mutations in CASR are causative in familial (benign) hypocalciuric hypercalcemia. In addition, polymorphisms in CASR can lead to either gain (R990G) or loss (A986S) of the receptor's function. Importantly, CASR has been implicated in the etiology of chronic pancreatitis in patients with a coexisting mutation in SPINKl (Felderbauer et ah, BMC Gastroenterology 5:34 (2003)).
  • HapMap tag SNPs 1 tag SNPs picked out for population CEU
  • HapMap tag SNPs 1 tag SNPs picked out for population CEU Chr7: 141985492..141989077 using the algorithm-Tagger-pairwiseTagging #tag SNPs Chromosome Pos maf rs3888796 Chr7 141987517 0.305 CASR Calcium-sensing Receptor
  • HapMap tag SNPs 12 tag SNPs picked out for population CEU Chr3:123386625..123486624 using the algorithm-Tagger-pairwiseTagging
  • HapMap tag SNPs 5 tag SNPs picked out for population CEU
  • HapMap tag SNPs 1 tag SNPs picked out for population CEU Chrl7:29606408..29608330 using the algorithm-Tagger-pairwiseTagging
  • HapMap tag SNPs 1 tag SNPs picked out for population CEU Chr4:74971309..74974465 using the algorithm-Tagger-pairwiseTagging
  • HapMap tag SNPs 4 tag SNPs picked out for population CEU Chrl 9: 10242778..10258290 using the algorithm-Tagger-pairwiseTagging
  • HapMap tag SNPs 14 tag SNPs picked out for population CEU Chr7:94571638..94598494 using the algorithm-Tagger-pairwiseTagging

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Hospice & Palliative Care (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des procédés permettant d’identifier les patients présentant un risque élevé de souffrir de toxicité médicamenteuse pancréatique, et implique l’analyse de certains polymorphismes touchant un nucléotide unique chez le patient. L’invention porte également sur des kits contenant des oligonucléotides pouvant être utilisés dans cette analyse.
PCT/US2009/052019 2008-07-31 2009-07-28 Marqueurs pharmacogénétiques de la prédisposition à la toxicité médicamenteuse pancréatique WO2010014651A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12994408P 2008-07-31 2008-07-31
US61/129,944 2008-07-31

Publications (1)

Publication Number Publication Date
WO2010014651A1 true WO2010014651A1 (fr) 2010-02-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120269799A1 (en) * 2011-03-24 2012-10-25 Muralidhar Reddy Moola Diagnostic and treatment methods using a ligand library
RU2582968C2 (ru) * 2014-07-16 2016-04-27 Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук Способ прогнозирования эффективности лечения злокачественного заболевания цисплатином

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6783961B1 (en) * 1999-02-26 2004-08-31 Genset S.A. Expressed sequence tags and encoded human proteins
US6828097B1 (en) * 2000-05-16 2004-12-07 The Childrens Mercy Hospital Single copy genomic hybridization probes and method of generating same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6783961B1 (en) * 1999-02-26 2004-08-31 Genset S.A. Expressed sequence tags and encoded human proteins
US6828097B1 (en) * 2000-05-16 2004-12-07 The Childrens Mercy Hospital Single copy genomic hybridization probes and method of generating same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Genetic cariation at the calcium-sensing receptor (CASR) locus: implications for clinical molecular diagnostics", CLINICAL BIOCHEMISTRY, vol. 40, 2007, pages 551 - 561 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120269799A1 (en) * 2011-03-24 2012-10-25 Muralidhar Reddy Moola Diagnostic and treatment methods using a ligand library
US9804168B2 (en) 2011-03-24 2017-10-31 Opko Pharmaceuticals, Llc Biomarker discovery in complex biological fluid using bead or particle based libraries and diagnostic kits and therapeutics
RU2582968C2 (ru) * 2014-07-16 2016-04-27 Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук Способ прогнозирования эффективности лечения злокачественного заболевания цисплатином

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